• Dyspeptic symptoms: bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning
• Secondary dyspepsia: structural/systemic/metabolic disease identified
• FD: no explanation found after diagnostic procedures
• PDS/EPS specifiers used based on symptom profile

• RFGES prevalence: 7.2% (95% CI 7.0–7.4) for FD symptoms

Must fulfill both:

1. One or more: bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning

2. No evidence of structural/systemic/metabolic disease explaining symptoms

• Criteria: last 3 months, onset ≥6 months before diagnosis

Required (≥2 days/week):

• Bothersome postprandial fullness (impacts usual activities)
• OR bothersome early satiation (prevents finishing regular-sized meal)

Associated features:

• Other food-induced symptoms allowed: postprandial epigastric pain/burning, nausea, bloating, excessive belching
• Predominant nausea/persisting vomiting → exclude PDS, consider CNVS/gastroparesis
• Heartburn not a gastroduodenal symptom but may coexist
• Postprandial = symptoms within 2 hours of meal intake

Required (≥1 day/week):

• Bothersome epigastric pain OR epigastric burning (impacts usual activities)
• Can be postprandial or meal-independent
• PDS criteria not fulfilled
• Predominant nausea/vomiting → exclude EPS

Provisional subcategories:

• Meal-related EPS: epigastric pain/burning worsens after meals in ≥50% of times
• Meal-unrelated EPS: worsening in <50%

• Impaired gastric accommodation (IGA): found in up to 40% of FD patients → leads to altered meal distribution toward distal stomach
• IGA associated with: early satiation, postprandial fullness, unintentional weight loss
• Delayed gastric emptying: ~30% of FD patients → associated with more severe upper GI symptoms (especially postprandial fullness, nausea, vomiting)
• Visceral hypersensitivity: up to 30% of FD patients → initially correlated to EPS, also associated with meal-related symptom severity
• Chemical stimuli (acid, nutrients, lipids) impact visceral sensitivity
• Altered gut peptide release affects gastroduodenal motility

• Barrier dysfunction: linked to increased mucosal permeability and immune activation
• Meta-analysis: higher duodenal eosinophils and mast cells in FD, more pronounced in post-infection FD
• Budesonide treatment → reduction in duodenal eosinophils correlates with symptom reduction (postprandial fullness, early satiation)
• PPI use in FD → decreased eosinophil/mast cell counts, improved barrier function, decreased symptom severity

• Duodenal biopsies show differences in bacterial phyla: Firmicutes, Fusobacteriota, Patescibacteria vs controls
• Overlapping IBS and PPI use are potential confounders

• Ratio of fasting primary:secondary bile salts decreased in FD vs healthy subjects
• Bile salt concentration correlates with impaired duodenal permeability
• Vitamin D receptor (bile acid sensor) expression increased in FD
• Inverse correlation between GE rate and duodenal bile salts

• Most FD patients report food-triggered/aggravated symptoms
• FODMAP elimination: beneficial effect on symptoms + improved intraepithelial flux across duodenal mucosa
• Confocal laser endomicroscopy: food induces acute immune reactions (eosinophils) in duodenal mucosa
• 6-food elimination diet: beneficial effect in FD

• Low-grade inflammation linked to neuro-immune dysregulation
• Mast cells show closer proximity to duodenal submucosal nerve endings in FD → correlates with GI symptom numbers and epigastric pain
• Eosinophil/mast cell counts in submucous plexus correlate with submucosal neuronal structural/functional damage

• Dysregulated duodenal hypothalamic-pituitary-adrenal (HPA) axis signaling in FD

• Clear associations between psychological comorbidities and FD
• Symptom severity and weight loss associated with psychosocial factors and somatization
• History of abuse → alterations in gastric sensorimotor function + PDS symptoms
• FD patients perceive life events as more stressful
• Bidirectional interaction between FD symptoms and psychological comorbidities over time

• FD has weak heritability
• Meta-analysis: no association with specific single nucleotide polymorphisms
• Inconsistencies between candidate gene studies

• Acute gastroenteritis (bacteria, viruses, parasites) → increased FD risk
• Post-infection onset associated with weight loss and early satiety
• Meta-analysis: increased duodenal eosinophils in post-infection FD vs controls

• H. pylori gastritis with characteristic findings (Kyoto classification) → considered organic disease
• Eradication therapy effective in ~30% of FD patients with NNT = 15
• If symptom remission persists ≥6 months after eradication → diagnosed as H. pylori-associated dyspepsia (HpD)

• Management guided by patient history
• In absence of alarm features: discontinue unnecessary drugs/supplements causing dyspepsia before further testing
• H. pylori status must be determined in every dyspeptic patient

• Routine laboratory testing (including celiac serology): not recommended due to low diagnostic yield
• No international consensus on routine duodenal biopsies
• Standard clinical practice: uninvestigated dyspepsia managed without upper endoscopy if no alarm features
• Upper endoscopy mandatory for: alarm features, clinical trial, mechanistic trial
• No evidence supporting routine imaging in FD diagnostic workup
• Additional testing considered for: abnormal clinical examination, failed treatment (case-by-case)
• Motility studies in routine FD diagnosis: not recommended

• Evidence for diet as therapeutic strategy: low
• Reasonable advice: frequent small-size meals, avoid high-fat foods

• Consider H. pylori as cause if eradication → sustained symptom benefit

• First-line for FD patients symptomatic after H. pylori eradication or H. pylori-negative
• Standard once-daily dose for 4–8 weeks, discontinue if insufficient improvement
• No dose escalation strategy recommended
• NNT = 11 for global symptom reduction
• Evidence limited in FD subgroups, no data in EPS-PDS overlap group
• PPI may be less effective for PDS symptoms

• NNT = 7, but low study quality, inclusion of GERD patients likely
• Most guidelines suggest PPI over H2RA as first-line (except NICE guidelines: both options)

• Heterogeneous class: anti-emetic properties (D2 antagonists) or prokinetic activity (5-HT4 agonists, cholinesterase inhibitors)
• Meta-analysis

• Meta-analysis demonstrated significant effect in reducing dyspeptic symptoms with NNT = 12 (excluding cisapride)
• 5-HT4 agonists: tegaserod showed benefit in female FD patients
• Itopride (D2 antagonist + cholinesterase inhibitor): significantly more responders based on global efficacy measure and Leuven postprandial distress scale in PDS-EPS overlap (Rome III)
• Acotiamide (cholinesterase inhibitor, M1/M2 muscarinic antagonist): enhances gastric accommodation and GE rate, well-tolerated, most effective for PDS

• Centrally acting neuromodulators effective for FD with NNT = 6
• Beneficial effect limited to tricyclic antidepressants (TCA) and antipsychotics (e.g., levosulidazole with prokinetic activity)
• Longest therapy duration: 12 weeks → long-term efficacy unknown
• Both adverse event number and withdrawal rates higher with psychotropic drugs
• Amitriptyline effects on pain potentially more useful in EPS
• Two SSRI studies in FD: negative
• Mirtazapine: improves early satiation scores, nutrient tolerance, associated with significant weight loss recovery, QoL improvement, reduced GI-specific anxiety
• Tandospirone citrate (5-HT1A agonist): improves abdominal symptom score, overall dyspeptic severity, individual symptoms (postprandial fullness, early satiation, upper abdominal bloating); increases gastric accommodation and delays GE of liquids
• Meta-analysis: FD patients treated with 5-HT4 or 5-HT1A agonists show significantly greater symptom improvement vs placebo

• STW 5 and STW 5-II: superior to placebo in FD treatment
• Peppermint oil + caraway oil combination: superior to placebo
• Rikkunshito (Japanese herbal KAMPO preparation): efficacy and safety in FD
• Zhi Zhu KuangZhong: symptom-reducing effect in PDS
• Biling Weitong granules: superior to placebo in reducing epigastric pain severity in EPS

• Lactobacillus gasseri OLL2716 (LG21): daily intake for 3 months → higher improvement rates for PDS symptoms (not EPS)
• Bacillus subtilis + coagulans strains: effective for key individual FD symptoms
• Review summarizes probiotic effects in FD

• At least 4 studies on CBT: all showed positive short-term effects on FD symptoms
• One study: sustained efficacy after 6 months follow-up
• Positive results of hypnotherapy in FD reported in one small RCT

• Meta-analyses of numerous low-quality RCTs suggest manual and electric acupuncture effective in FD treatment
• Major concerns: selection bias, performance bias, reporting bias, attrition bias

• Dietary/lifestyle advice precedes pharmacotherapy
• First-line: PPI, first-line prokinetic agents, or herbal preparations (STW 5, STW 5-II, rikkunshito, peppermint oil/caraway oil, or better-studied Chinese herbal medicines) → choice depends on clinical experience and agent availability
• Insufficient response: endoscopy and other tests recommended if not yet performed
• Second-line: neuromodulators
• Refractory early satiation → consider 5-HT1A agonist (tandospirone or buspirone)
• Weight loss → mirtazapine option
• TCA may show efficacy for postprandial fullness
• Non-responders: consider GE test → if significant delay, second-line prokinetic agents (prucalopride, levo-sulpiride) → classified as "PDS with delayed GE"
• Gastroparesis term reserved for predominant nausea or recurrent vomiting

• Dietary/lifestyle advice precedes pharmacotherapy
• First-line: PPI or herbal preparations with established efficacy/safety profile
• Insufficient response: endoscopy and other tests recommended if not yet performed
• Second-line: neuromodulators, specifically TCA
• Both EPS and PDS: nutritional support recommended for refractory symptoms with weight loss or feeding restrictions

• Nausea: unpleasant sensation of impending need to vomit
• Vomiting: forceful oral expulsion of GI contents from mouth (distinguished from regurgitation = effortless passage)
• Diagnostic approach to chronic/recurrent nausea/vomiting: see Figure 5

Must include ALL:

1. Bothersome nausea ≥2 days/week with or without ≥1 vomiting episode/week

2. Exclude: self-induced vomiting, eating disorders, regurgitation, rumination as cause

3. No evidence of structural/systematic/metabolic disease on routine investigations

4. Symptoms predominantly due to PDS → exclude diagnosis

5. Predominant nausea/persistent vomiting with delayed GE → prompt gastroparesis diagnosis

• Criteria: last 3 months, onset ≥6 months before diagnosis

Must include ALL:

1. Stereotypical repetitive vomiting episodes regarding onset (acute) and duration (up to 10 days)

2. ≥3 discrete episodes in prior year, ≥2 episodes in past 6 months, occurring ≥1 week apart

3. Milder symptoms (nausea, isolated vomiting) can be present between cycles

• Supportive: history or family history of migraine headaches

Must include ALL:

1. Stereotypical episodic vomiting resembling CVS in onset, duration, frequency

2. Presentation after prolonged (≥1 year) and excessive (≥4 days/week and/or ≥15 doses/week) cannabis use

3. Relief of vomiting episodes by sustained (≥6 months or 3 typical emetic cycles) cessation of cannabis use

• Supportive: may be associated with pathologic bathing behavior (prolonged hot baths/showers)

• Symptom frequency changed to >2 nausea days weekly with or without >1 weekly vomiting episodes
• Question PDS symptoms when evaluating for CNVS → PDS diagnosis if dominant
• Delayed GE with CNVS symptoms → prompt gastroparesis diagnosis

• Minor changes: acknowledge some patients experience minor vomiting during interepisodic phases

• Quantified cannabis-use profiles and durations of abstinence for diagnosis

• Unexplained vomiting ≥once monthly: 2–3% of individuals
• Nausea ≥weekly: 3%
• RFGES: nausea without vomiting reported by 1.9% of responders (unpublished) → more common in women and those <40 years
• Rome IV survey: CNVS prevalence 0.8–1.2%
• Associated with IBS (41%) and FD (55%)
• Reduced quality of life

• Rome IV survey: prevalence 1.4% → greater in US vs Canada/UK
• Japan prevalence lower: 0.05 cases/1,000 population
• Mean age of onset: 32 years
• More common in women

• Debated whether CHS is CVS subtype or distinct entity
• Advocacy for distinct diagnosis: pathophysiology and treatment differ from CVS
• Up to 80% of CVS patients use cannabis to relieve vomiting/abdominal pain during attacks (likely not CHS)
• Overall prevalence: 0.12%; US populations: 0.4%
• Cannabis use among CVS patients increased 10-fold (2005–2014)
• 18% of CVS patients, 39% of cannabis-using CVS patients have CHS
• More common in men; median diagnosis age: 28 years
• >4 year diagnostic delay in 40% of patients
• One review: 22% used cannabis >11 years, 17% for 6–10 years, 36% for 2–5 years
• Cannabis use: ≥daily in 61%, weekly in 19%
• Diagnoses doubled (2000–2015) → likely due to higher THC content products

• Multifactorial
• Insular cortex, amygdala, putamen, pons, other cortical regions contribute to nausea perception
• Dorsal vagal complex and vagal pathways regulate vomiting
• Most studies: poor correlation of delayed GE to nausea/vomiting severity
• One study: FD patients with normal GE had nearly identical symptoms to gastroparesis patients with delayed GE
• GE labile: >1/3 of patients switched GE rate group at 48 weeks follow-up
• Review restricting GE analyses to optimal methods: delayed GE correlated with nausea, vomiting, early satiety/fullness, abdominal pain (OR 1.5–2.94)
• Histopathologic findings from full-thickness gastric specimens: poorly relate to GE; similar reductions in interstitial cell of Cajal populations in delayed vs normal GE

• Occurs in isolation or with GI, neurohumoral, autonomic, genetic factors
• Rapid GE found in 40–80% of CVS patients between vomiting episodes
• Delayed GE described in 27%
• Autonomic abnormalities and sympathetic dysfunction prevalent
• Personal/family histories of migraines often reported
• CVS flares in some women begin before menstruation (catamenial CVS)
• Some cases exhibit maternal inheritance → suggests mitochondrial DNA abnormalities
• Associated genetic factors:
• Polymorphisms of

• Polymorphisms of cannabinoid and μ-opioid receptor genes
• Single-nucleotide mitochondrial DNA polymorphisms (16159T and 3010A)
• Calcium channel gene type-2 ryanodine receptor mutations
• Endocannabinoid-related lipids and salivary cortisol elevated during emetic episodes

Triggers of flares:

• Psychological stress and catastrophizing
• Physiological stressors: infection, altered food intake, exercise, impaired sleep
• Food triggers: cheese, cured meats, chocolate, monosodium glutamate

Psychiatric comorbidity: 78% of adults with CVS screen positive for depression, 84% positive for anxiety

• Multifactorial mechanisms for symptom induction
• THC contributes to both antiemetic and proemetic actions of cannabis
• Postulated: CHS results from downregulation, desensitization, or internalization of CB1 receptors in HPA axis and sympathetic nervous system
• Changes in TRPV1 receptor function also prominent
• 59% of CHS patients screen positive for anxiety, 68% positive for depression

Differential diagnosis includes:

• Gastroparesis, mechanical obstruction, metabolic disorders, autoimmune disease, infiltrative disorders, psychiatric illnesses, intracranial masses, inner ear disease, medications
• Role of chronic cannabis use as cause of CNVS: controversial

Diagnostic testing dictated by clinical presentation:

• Bilious vomiting, abdominal tenderness, abnormal neurological findings, worsening vomiting → warrants evaluation
• Blood work: excludes electrolyte abnormalities and metabolic disorders
• Endoscopy or imaging: evaluates for organic disease
• Specialized GI function tests: offered in selected settings

Four phases characterized:

1. Prodrome: nausea, abdominal pain, fatigue, weakness → initial presentation, can be stereotypical in timing

2. Emetic phase: 3–6 days, unrelenting vomiting >8 times/hour on average → within minutes to hours after prodrome

• Nearly 2/3 report abdominal pain and diarrhea during this phase

3. Recovery phase: up to 1 week → persistence of nausea, lightheadedness, meal intolerance in some patients

4. Interepisodic phase: weeks to months duration

Additional findings:

• Up to 63% of CVS patients have milder nausea, dyspepsia, intermittent vomiting between attacks
• Fluid loss, electrolyte abnormalities, hematemesis may occur acutely
• Dental enamel damage with repeated attacks
• Compulsive hot bathing behavior: 48% of CVS patients who do not use cannabis

Diagnostic testing: performed only to exclude other causes of chronic nausea/vomiting → negligible yield

Four phases similar to CVS:

• Acute emetic phases: few hours to 1 week, vomiting >20 times daily with abdominal pain, diarrhea, autonomic symptoms
• One review: up to 18% of cases not characterized as episodic emesis → possibility that not all CHS cases mimic CVS

Compulsive bathing behaviors: 92% of patients report to reduce vomiting and pain during attacks

Factors associated with CHS diagnosis:

• Cannabis use >1 year
• Daily cannabis use, weekly cannabis use
• Symptom resolution with cannabis abstinence
• Compulsive bathing to relieve symptoms
• Male sex, age <50 years

Diagnostic challenges: confirming symptom resolution after cannabis cessation → roadblock in many cases

• Only 19% able to abstain from cannabis for >4 weeks
• Cannabis metabolites persist >1 month; brain impairments may endure longer
• Proposed: cannabis cessation >6 months or >3 typical CHS cycles for diagnosis

Testing: rarely indicated in absence of complications (e.g., hemorrhage)

• Urine drug testing for THC metabolites: considered for patients who deny cannabis use
• No metabolite profile specific for CHS

• Little investigation on CNVS treatment
• Antiemetic agents: antagonists of H1, D2, 5-HT3, neurokinin (NK)1 receptors; agonists of cannabinoid CB1 receptors
• Other therapies: TCA and psychological measures show benefits in some patients
• Limited data supporting ginger, herbal remedies, electroacupuncture

Abortive treatment: may not be feasible if prodrome is short; non-oral treatments most likely beneficial after emesis starts

• 5-HT3 antagonist ondansetron: commonly used for CVS attacks, but no trials specifically in CVS
• NK1 antagonists (aprepitant, fosaprepitant): reduce emesis frequency and hospitalizations in refractory patients
• Sedating agents: benzodiazepines, H1 antagonists → often beneficial adjuncts to antiemetics
• Intranasal or injectable triptans: reduce vomiting and abdominal pain, especially with family migraine histories

Preventive treatment:

• TCA: improvements in 69% of CVS patients
• Poor responses in those with migraines, psychological illness, cannabis or opioid use
• Topiramate (anticonvulsant): reduced attacks and healthcare utilization in 65% of patients
• Patients refractory to TCA: 50% fewer CVS attacks on zonisamide or levetiracetam
• Mitochondrial supplements (coenzyme Q10, L-carnitine, riboflavin): some prophylactic efficacy
• Psychological therapy: CBT advocated for some patients
• Integrative health care model (mediation + care coordination): superior outcomes

• Several reports confirm cannabis cessation leads to CHS resolution
• Resuming cannabis use promotes symptom resurgence
• CBT: may help reduce cannabis dependence in CHS

Abortive therapies:

• Cutaneous capsaicin (TRPV1 agonist): shortens CHS episodes, decreases therapy requirements
• Hot showers: activate skin TRPV1 thermoreceptors → plausible mechanism for benefit
• Parenteral D2 antagonists haloperidol and droperidol: efficacy in aborting CHS episodes (uncontrolled series + controlled trial)
• Benzodiazepines (lorazepam, alprazolam): relief in small series

Preventive therapy: CHS responds poorly to TCA

• One small series: effective prophylaxis with olanzapine

• Belching (eructation, ructus): audible escape of gaseous material from esophagus or stomach into pharynx
• Two distinct types: gastric belch and supragastric belch
• Disorder only when excessive and bothersome (applies to both types)

• RFGES: overall prevalence of Rome IV belching disorders = 1%
• Referred patients with upper GI symptoms: prevalence several times higher

• B3a: Supragastric Belching (from esophagus)
• B3b: Gastric Belching (from stomach)

1. Supragastric belching strongly supported by observing frequent, repetitive belching

2. Supragastric belching can be interrupted by maneuvers or distraction

3. Excessive gastric belching: no defining clinical correlate

4. Intraluminal esophageal impedance measurement (with or without manometry): allows objective differentiation of supragastric vs gastric belches

• Criteria: last 3 months, onset ≥6 months prior to diagnosis

• Physiological reflex triggered by distension of proximal stomach
• Results in transient relaxation of lower esophageal sphincter (TLESR)
• Rapid distension of esophagus by large volume of gas → relaxation of upper esophageal sphincter (UES)
• Gaseous distension caused by: air swallowing, ingestion of carbon dioxide source, mechanical inflation (respirator, sleep apnea equipment)

• Eructated air does not originate from stomach → either sucked or (less commonly) injected into esophagus from pharynx, then expelled immediately
• Not accompanied by TLESR
• Occasional supragastric belching: occurs in most healthy subjects
• Patients with excessive supragastric belching: more belching events but do not swallow more air than gastric belchers

• Patients with excessive supragastric belching: significantly impaired health-related QoL → primarily social function and vitality impairments
• High prevalence of anxiety disorders
• Symptoms aggravated during stressful events
• Distraction reduces belching frequency; drawing attention increases frequency

• Belching: one of most frequently reported symptoms in GERD patients (after heartburn and regurgitation)
• Partially explained by higher incidence of air swallows and higher frequency of gastric belching
• Study comparing Rome IV excessive belching patients with GERD patients: most common type in both groups was supragastric (93% vs 87%)
• Several groups described temporal relationship between supragastric belches and reflux events → subject's response to unpleasant sensation
• Incidence of these belches diminished by acid suppressive treatment
• Opposite sequence (supragastric belch first, reflux second) also found more often than expected
• Hypothesis: supragastric belches can provoke reflux in subset of patients
• Supported by observation: treatment of supragastric belching with CBT reduces acid reflux